U.S. patent number 8,754,214 [Application Number 14/096,191] was granted by the patent office on 2014-06-17 for synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates.
This patent grant is currently assigned to Shionogi & Co., Ltd., ViiV Healthcare Company. The grantee listed for this patent is Shionogi & Co., Ltd., ViiV Healthcare Company. Invention is credited to Brian Alvin Johns, Takashi Kawasuji, Daiki Nagamatsu, Yoshiyuki Taoda, Hiroshi Yoshida.
United States Patent |
8,754,214 |
Yoshida , et al. |
June 17, 2014 |
Synthesis of carbamoylpyridone HIV integrase inhibitors and
intermediates
Abstract
A synthesis approach providing an early ring attachment via a
bromination to compound I-I yielding compound II-II: ##STR00001##
whereby a final product such as AA: ##STR00002## can be
synthesized. In particular, the 2,4-difluorophenyl-containing
sidechain is attached before creation of the additional ring Q.
Inventors: |
Yoshida; Hiroshi (Osaka,
JP), Taoda; Yoshiyuki (Osaka, JP), Johns;
Brian Alvin (Research Triangle Park, NC), Kawasuji;
Takashi (Osaka, JP), Nagamatsu; Daiki (Osaka,
JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
Shionogi & Co., Ltd.
ViiV Healthcare Company |
Osaka
Research Triangle Park |
N/A
NC |
JP
US |
|
|
Assignee: |
Shionogi & Co., Ltd.
(Osaka, JP)
ViiV Healthcare Company (Research Triangle Park,
NC)
|
Family
ID: |
42242992 |
Appl.
No.: |
14/096,191 |
Filed: |
December 4, 2013 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20140094605 A1 |
Apr 3, 2014 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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13128992 |
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8624023 |
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PCT/US2009/006422 |
Dec 8, 2009 |
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61193634 |
Dec 11, 2008 |
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Current U.S.
Class: |
544/343;
544/95 |
Current CPC
Class: |
C07D
471/22 (20130101); A61K 31/351 (20130101); C07D
213/81 (20130101); C07D 487/22 (20130101); A61K
31/4412 (20130101); A61P 31/18 (20180101); C07D
213/803 (20130101); C07D 498/14 (20130101); A61P
43/00 (20180101); Y02P 20/55 (20151101) |
Current International
Class: |
C07D
498/14 (20060101); C07D 471/22 (20060101) |
Field of
Search: |
;544/343 |
References Cited
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WO |
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Feb 2012 |
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WO |
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|
Primary Examiner: Habte; Kahsay
Attorney, Agent or Firm: Wenderoth, Lind & Ponack,
LLP.
Claims
What is claimed is:
1. A compound of the following formula (DD): ##STR00047## wherein
P.sup.1 is H or a carboxy protecting group.
2. The compound of claim 1, wherein P.sup.1 is benzyl.
Description
FIELD OF THE INVENTION
The present invention comprises modifications of known processes
for synthesizing compounds having HIV integrase inhibitory
activity.
BACKGROUND OF THE INVENTION
WO 2006/116764 published 2 Nov. 2006, incorporated by reference in
its entirety, describes various compounds and detailed synthetic
schemes for their preparation. In particular, a reaction sequence
is depicted at page 79 thereof wherein
3-benzyloxy-2-methyl-1H-pyridine-4-one of formula 3 is there
brominated to the bromopyridine 4 there, which is then reacted with
methanol and carbon monoxide to yield the nicotinic acid methyl
ester 5 there which is after several steps reacted with a
benzylamine to create the amide side chain-containing pyridine 10.
Thus, the amide sidechain is in place before creation of the
Z.sup.1Z.sup.2 ring of the final product formula (I) therein in the
reaction depicted at page 80 from 16 to 17-1.
A second reaction sequence is depicted at page 113 of WO
2006/116764 wherein a pyrrolidine compound 102 is allowed to
condense into a tricyclic compound 103 which is then brominated to
yield the bromine compound 104 which is then reacted with a
benzylamine to create the amide side chain-containing tricyclic
compound 105 therein. Thus, the bromination takes place after
creation of the Z.sup.1Z.sup.2 ring of the final product of formula
(I) therein.
N-Methoxy-N-methyl amides may be prepared by Pd catalyzed
aminocarbonylation of aryl bromides as described by J. R.
Martinelli et al in Organic Letters, Vol. 8, No. 21, pages
4843-4846 (2006). Bromoanilines and bromoanisoles are converted to
esters as described by J. Albaneze-Walker et al in Organic Letters,
Vol. 6, No. 13, pages 2097-2100 (2004).
SUMMARY OF THE INVENTION
Processes are provided which utilize an early bromination step in
the construction of compounds useful as having HIV integrase
inhibitory activity as set forth in WO 2006/116764. The bromination
provides the leaving group for attachment of an amide side chain on
a pyridone ring.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows an X-ray power diffraction pattern of a crystal of
compound 13.
FIG. 2 shows an infrared absorption spectra of a crystal of
compound 13.
FIG. 3 shows a solid state .sup.13C-NMR spectra of a crystal of
compound 13.
FIG. 4 shows an X-ray powder diffraction pattern of a crystal of
compound 13b (monohydrate form of compound 13).
FIG. 5 shows an infrared absorption spectra of a crystal of
compound 13b (monohydrate form of compound 13).
FIG. 6 shows an X-ray powder diffraction pattern of a crystal of
compound 12.
FIG. 7 shows an infrared absorption spectra of a crystal of
compound 12.
DETAILED DESCRIPTION OF THE INVENTION
A process is provided within a synthesis of a pyridone compound of
the following formula (AA), (BB) or (CC):
##STR00003##
##STR00004##
##STR00005##
comprising the steps of: P-1) brominating a compound of the
following formula (I-I) to produce a bromine compound of the
following formula (II-II):
##STR00006## wherein R is --CHO, --CH(OH).sub.2,
--CH(OH)(OR.sup.4), --CH(OH)--CH.sub.2OH or
--CH(OR.sup.5)(OR.sup.6); P.sup.1 is H or a hydroxyl protecting
group; P.sup.3 is H or a carboxy protecting group; R.sup.4 is lower
alkyl; R.sup.5 and R.sup.6 are independently lower alkyl or R.sup.5
and R.sup.6 can be lower alkyl and joined to form a 5-, 6-, or
7-membered ring, and P-2) creating the
2,4-di-fluorophenyl-CH.sub.2--NH--C(O)-- sidechain with the
reactants 2,4-di-fluorophenyl-CH.sub.2--NH.sub.2 and carbon
monoxide.
The term "lower alkyl", alone or in combination with any other
term, refers to a straight-chain or branched-chain saturated
aliphatic hydrocarbon radical containing 1 to 6 carbon atoms.
Examples of alkyl radicals include, but are not limited to, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isoamyl, n-hexyl and the like.
The term "lower cycloalkyl" refers to a saturated or partially
saturated carbocyclic ring composed of 3-6 carbons in any
chemically stable configuration. Examples of suitable carbocyclic
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and cyclohexenyl.
The term "lower alkenyl," alone or in combination with any other
term, refers to a straight-chain or branched-chain alkyl group with
one or two carbon-carbon double bonds. Examples of alkenyl radicals
include, but are not limited to, ethenyl, propenyl, isopropenyl,
butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl and the
like.
The term "lower alkylene" refers to a straight or branched chain
divalent hydrocarbon radical, preferably having from one to six
carbon atoms, unless otherwise defined. Examples of "alkylene" as
used herein include, but are not limited to, methylene, ethylene,
propylene, butylene, isobutylene and the like.
The term "lower alkenylene" refers to a straight or branched chain
divalent hydrocarbon radical, one or two carbon-carbon double
bonds.
The term "lower alkoxy" refers to an alkyl ether radical, wherein
the term "alkyl" is defined above. Examples of suitable alkyl ether
radicals include, but are not limited to, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy
and the like.
The term "halogen" refers fluorine (F), chlorine (Cl), bromine
(Br), or iodine (I).
The term "aryl" alone or in combination with any other term, refers
to a carbocyclic aromatic moiety (such as phenyl or naphthyl)
containing 6 carbon atoms, and more preferably from 6-10 carbon
atoms. Examples of aryl radicals include, but are not limited to,
phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl,
phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the
like. Unless otherwise indicated, the term "aryl" also includes
each possible positional isomer of an aromatic hydrocarbon radical,
such as in 1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl,
6-tetrahydronaphthyl, 1-phenanthridinyl, 2-phenanthridinyl,
3-phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl,
8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl.
Examples of aryl radicals include, but are not limited to, phenyl,
naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl,
tetrahydronaphthyl, indanyl, phenanthridinyl and the like. The term
"aralkyl" refers to an alkyl group substituted by an aryl. Examples
of aralkyl groups include, but are not limited to, benzyl and
phenethyl.
The term "heterocyclic group," and "heterocycle" as used herein,
refer to a 3- to 7-membered monocyclic heterocyclic ring or 8- to
11-membered bicyclic heterocyclic ring system any ring of which is
either saturated, partially saturated or unsaturated, and which may
be optionally benzofused if monocyclic. Each heterocycle consists
of one or more carbon atoms and from one to four heteroatoms
selected from the group consisting of N, O and S, and wherein the
nitrogen and sulfur heteroatoms may optionally be oxidized, and the
nitrogen atom may optionally be quaternized, and including any
bicyclic group in which any of the above-defined heterocyclic rings
is fused to a benzene ring. The heterocyclic ring may be attached
at any carbon or heteroatom, provided that the attachment results
in the creation of a stable structure. Preferred heterocycles
include 5-7 membered monocyclic heterocycles and 8-10 membered
bicyclic heterocycles. When the heterocyclic ring has substituents,
it is understood that the substituents may be attached to any atom
in the ring, whether a heteroatom or a carbon atom, provided that a
stable chemical structure results. "Heteroaromatics" or
"heteroaryl" are included within the heterocycles as defined above
and generally refers to a heterocycle in which the ring system is
an aromatic monocyclic or polycyclic ring radical containing five
to twenty carbon atoms, preferably five to ten carbon atoms, in
which one or more ring carbons, preferably one to four, are each
replaced by a heteroatom such as N, O, S and P. Preferred
heteroaryl groups include 5-6 membered monocyclic heteroaryls and
8-10 membered bicyclic heteroaryls. Also included within the scope
of the term "heterocycle, "heterocyclic" or "heterocyclyl" is a
group in which a non-aromatic heteroatom-containing ring is fused
to one or more aromatic rings, such as in an indolinyl, chromanyl,
phenanthridinyl or tetrahydro-quinolinyl, where the radical or
point of attachment is on the non-aromatic heteroatom-containing
ring. Unless otherwise indicated, the term "heterocycle,
"heterocyclic" or "heterocyclyl" also included each possible
positional isomer of a heterocyclic radical, such as in
1-indolinyl, 2-indolinyl, 3-indolinyl. Examples of heterocycles
include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl,
isoquinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl,
pyridazyl; pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl,
pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl,
piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl,
thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl,
tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone,
oxazolyl, oxadiazolyl, benzoxazolyl, oxopiperidinyl,
oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl, isothiazolyl,
furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl,
thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl,
dithiolyl, thiophenyl, tetrahydrothiophenyl, sulfolanyl, dioxanyl,
dioxolanyl, tetahydrofurodihydrofuranyl,
tetrahydropyranodihydrofuranyl, dihydropyranyl,
tetradyrofurofuranyl and tetrahydropyranofuranyl.
Optional substituents are hydroxy, halogen, amino and lower
alkyl.
Protecting groups may be selected from groups known to those
skilled in the art, including protecting groups disclosed in
Greene, Theodora W.; Wuts, Peter G. M. Protective Groups in Organic
Synthesis. 2nd Ed. (1991), 473 pp. or Kocienski, Philip J.
Protecting Groups. 3rd Ed. 2005, (2005), 679 pp.
The pyridone ring depicted in (I-I) and (II-II), ie to which the
--OP.sup.1 is directly attached, becomes in AA, BB and CC the ring
shown next to the Q ring as follows:
##STR00007##
Thus, the step P-2) can be carried out before or after creation of
the Q ring, such steps for the creation of the Q ring being
described herein and in WO 2006/1116764.
The present invention features a process as described above,
wherein said step P-2) is carried out before creation of the Q ring
and wherein said pyridone compound is of the formula AA or formula
BB or formula CC.
The present invention features a process as described above,
wherein said step P-2) is carried out after creation of the Q ring
and wherein said pyridone compound is of the formula AA or formula
BB or formula CC.
The present invention features a process as described above,
wherein the pyridone compound is of the formula AA.
The present invention features a process as described above,
wherein the pyridone compound is of the formula BB.
The present invention features a process as described above,
wherein the pyridone compound is of the formula CC.
Also part of the present invention are novel intermediates such as
those of the following formula (DD) below:
##STR00008##
wherein P.sup.1 is as described above, particularly benzyl.
A process is provided for the preparation of a pyridone compound of
the following formula (AA), (BB) or (CC):
##STR00009##
##STR00010##
##STR00011##
comprising the steps of: P-1) brominating a compound of the
following formula (I-I) to produce a bromine compound of the
following formula (II-II):
##STR00012## wherein R is --CHO; --CH(OH).sub.2,
--CH(OH)(OR.sup.4), --CH(OH)--CH.sub.2OH or
--CH(OR.sup.5)(OR.sup.6); P.sup.1 is H or a hydroxyl protecting
group; P.sup.3 is H or a carboxy protecting group; R.sup.4 is lower
alkyl; R.sup.5 and R.sup.6 are independently lower alkyl or R.sup.5
and R.sup.6 can be lower alkyl and joined to form a 5-, 6-, or
7-membered ring, P-2) creating the
2,4-di-fluorophenyl-CH.sub.2--NH--C(O)-- sidechain with the
reactants 2,4-di-fluorophenyl-CH.sub.2--NH.sub.2 and carbon
monoxide to form a compound of formula III-III
##STR00013## P-3) condensing and debenzylating a compound of
formula III-III to form a compound of formula AA, BB, or CC.
The present invention also features processes as described above
wherein P.sup.1 is benzyl; P.sup.3 is methyl; and R is --CHO,
--CH(OH)(OR.sup.4), --CH(OR.sup.5)(OR.sup.5) wherein R.sup.4 and
R.sup.5 are lower alkyl.
There is also described herein the process for the preparation of a
compound of the following formula (I):
##STR00014## wherein R is --CHO, --CH(OH).sub.2 or
--CH(OH)(OR.sup.4); P.sup.1 is H or a hydroxyl protecting group;
P.sup.3 is H or a carboxy protecting group; R.sup.3 is H, halogen,
hydroxy, optionally substituted lower alkyl, optionally substituted
cycloalkyl, optionally substituted lower alkenyl, optionally
substituted lower alkoxy, optionally substituted lower alkenyloxy,
optionally substituted aryl, optionally substituted aryloxy,
optionally substituted heterocyclic group, optionally substituted
heterocycleoxy and optionally substituted amino; R.sup.4 is lower
alkyl; R.sup.x is H, halo or R.sup.2--X--NR.sup.1--C(O)--; R.sup.2
is optionally substituted aryl; X is a single bond, a heteroatom
group selected from O, S, SO, SO.sub.2, and NH or loweralkylene or
lower alkenylene wherein each may be intervened by the heteroatom;
and R.sup.1 is H or lower alkyl,
which comprises the steps of: i) reacting a compound of formula
(II):
##STR00015## with an amine of formula (III) or (IV):
##STR00016## wherein R.sup.5 and R.sup.6 are independently lower
alkyl or R.sup.5 and R.sup.6 can be alkyl and joined to form a 5-,
6-, or 7-membered ring,
##STR00017##
to produce an intermediate of formula (V) or (VI),
respectively:
##STR00018##
##STR00019##
and ii) refunctionalizing (V) or (VI) to produce (I).
Specific compounds used in the processes include those of the
following formulae (IIa), (VIa), (VIb) and (Ia) utilized in
Examples which follow:
##STR00020##
##STR00021##
##STR00022##
##STR00023##
The product (Ia) of a synthetic sequence can be condensed with an
amine, eg of the formula H.sub.2NCH.sub.2CH.sub.2CH.sub.2OH,
brominated if. R.sup.x is H, carbonylated and amidated and finally,
debenzylated to yield a compound of WO 2006/116764 designated (I-7)
at page 240 wherein (R).sub.m is 4-F and R.sup.a is H.
Alternatively, such a compound may be synthesized by starting with
(I) where R.sup.x is p-F-phenyl-CH.sub.2--NH--C(O)--, R.sup.3 is H,
P.sup.1 is benzyl (Bn) and P.sup.3 is a carboxy protecting
group.
In more detail, step i) can be carried out out in a protic or
aprotic solvent such as EtOH, THF or DMF at a temperature of about
50-150.degree. C. for about 1-10 hours.
In more detail, step ii) can be carried out for the diol starting
material (VI) with an oxidizing agent such as NaIO.sub.4, RuO.sub.4
or Pb(OAc).sub.4 in a solvent such as H.sub.2O, MeOH or CH.sub.3CN
at ambient temperature for one or more hours. For the acetal type
starting material such as (V), reaction may be in an acid such as
HCl, CF.sub.3COOH or HCOH optionally with heating.
Step ii) can also involve refunctionalization at the R.sup.x
postion, eg R.sup.x=H to R.sup.x=Br optionally with further
refunctionalization to R.sup.x=R.sup.2--X--NR.sup.1--C(O)--. Step
ii) can also involve refunctionalization of P.sup.3, eg
P.sup.3.dbd.H to P.sup.3=Me.
In more detail, step P-1) can be carried out by treating a compound
of formula I-I with a bromine source including but not limited to
N-bromosuccinimide or bromine in a solvent such as N,N-dimethyl
formamide, THF or acetic acid and the like. This transformation can
be run particularly at a temperature of -10.degree. C. to
50.degree. C. to produce a compound of formula II-II.
In more detail, step P-2) can be carried out by treating a compound
of formula II-II with 2,4-difluorophenyl-CH.sub.2--NH.sub.2, carbon
monoxide, a suitable base and palladium (0) source and optionally
an appropriate ligand in an inert solvent optionally with heating.
The carbon monoxide can be at atmospheric pressure (14.7 psi) or at
elevated pressure particularly in the range of up to 60 psi but in
some cases higher pressures may be required. Bases include but are
not limited to tertiary amine bases such as diisopropylethylamine
and triethylamine and the like. Inorganic bases such as potassium
acetate and potassium phosphate are also bases of significance.
Suitable sources of Pd (0) include but are not limited to tetrakis
triphenylphosphine palladium (0). In some cases a Pd (II) precursor
can be used to generate Pd (0) in situ. Suitable Pd (II) precursors
include but are not limited to Pd(OAc).sub.2, Pd(OCOCF.sub.3).sub.2
and ligands include Xantphos, diphenylphosphinoferrocene (dppf),
triphenylphosphine and the like. Solvents include N,N-dimethyl
formamide, THF, toluene, DMSO and the like. Heating the mixture is
optionally used in the range from ambient to 150.degree. C.
The present invention also features crystalline forms of a compound
of formula AA (Compound 13, Example 1) salt and a hydrate thereof.
The present invention features:
(1) A salt or a hydrate thereof of a compound of formula AA:
##STR00024##
(2) A crystal form of a sodium salt or a hydrate thereof of a
compound of formula AA:
##STR00025##
(3) A crystal form of (2) having one or more physical properties
selected from the group consisting of (i) and (ii): (i) having
characteristic diffraction peaks at 6.4.degree..+-.0.2.degree.,
9.2.degree..+-.0:2.degree., 13.8.degree..+-.0.2.degree.,
19.2.degree..+-.0.2.degree. and 21.8.degree..+-.0.2.degree. degrees
two-theta in an X-ray powder diffraction pattern; and (ii) having
characteristic infrared absorption spectra at 1641 cm.sup.-1.+-.2
cm.sup.-1, 1536 cm.sup.-1.+-.2 cm.sup.-1, 1503 cm.sup.-1.+-.2
cm.sup.-1 and 1424 cm.sup.-1.+-.2 cm.sup.-1.
(4) A crystal form of (2) having characteristic diffraction peaks
at 6.4.degree..+-.0.2.degree., 9.2.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., 19.2.degree..+-.0.2.degree. and
21.8.degree..+-.0.2.degree. degrees two-theta in an X-ray powder
diffraction pattern.
(5) A crystal form of (2) having characteristic diffraction peaks
at 6.4.degree..+-.0.2.degree., 9.2.degree..+-.0.2.degree.,
13.8.degree..+-.0.2.degree., 14.6.degree..+-.0.2.degree.,
15.2.degree..+-.0.2.degree., 17.6.degree..+-.0.2.degree.,
19.2.degree..+-.0.2.degree., 21.8.degree..+-.0.2.degree.,
24.1.degree..+-.0.2.degree. and 28.7.degree..+-.0.2.degree. degrees
two-theta in an X-ray powder diffraction pattern.
(6) A crystal form of (2) having characteristic infrared absorption
spectra at 1641 cm.sup.-1.+-.2 cm.sup.-1, 1536 cm.sup.-1.+-.2
cm.sup.-1, 1503 cm.sup.-1.+-.2 cm.sup.-1 and 1424 cm.sup.-1.+-.2
cm.sup.-1.
(7) A crystal form of (2) having characteristic infrared absorption
spectra at 1641 cm.sup.1.+-.2 cm.sup.-1, 1536 cm.sup.-1.+-.2
cm.sup.-1, 1503 cm.sup.-1.+-.2 cm.sup.-1, 1424 cm.sup.1.+-.2
cm.sup.-1, 1282 cm.sup.-1.+-.2 cm.sup.-1, 1258 cm.sup.1.+-.2
cm.sup.-1, 1093 cm.sup.-1.+-.2 cm.sup.-1 and 1069 cm.sup.-1.+-.2
cm.sup.-1.
(8) A crystal form of (2) having one or more spectra selected from
the group consisting of (a) to (c):
(a) X-ray powder diffraction pattern substantially as shown in FIG.
1;
(b) Infrared absorption spectra substantially as shown in FIG. 2;
and
(c) Solid state .sup.13C-NMR spectra substantially as shown in FIG.
3.
(9) A crystal form of (2) having one or more physical properties
selected from the group consisting of (iii) and (iv): (iii) having
characteristic diffraction peaks at 8.0.degree..+-.0.2.degree.,
9.3.degree..+-.0.2.degree., 11.3.degree..+-.0.2.degree.,
16.0.degree..+-.0.2.degree., and 22.8.degree..+-.0.2.degree.
degrees two-theta in an X-ray powder diffraction pattern; and (iv)
having characteristic infrared absorption spectra at 1637
cm.sup.-1.+-.2 cm.sup.-1, 1536 cm.sup.-1.+-.2 cm.sup.-1, 1501
cm.sup.-1.+-.2 cm.sup.-1 and 1422 cm.sup.1.+-.2 cm.sup.-1.
(10) A crystal form of (2) having characteristic diffraction peaks
at 8.0.degree..+-.0.2.degree., 9.3.degree..+-.0.2.degree.,
11.3.degree..+-.0.2.degree., 16.0.degree..+-.0.2.degree. and
22.8.degree..+-.0.2.degree. degrees two-theta in an X-ray powder
diffraction pattern.
(11) A crystal form of (2) having characteristic diffraction peaks
at 8.0.degree..+-.0.2.degree., 9.3.degree..+-.0.2.degree.,
11.3.degree..+-.0.2.degree., 15.4.degree..+-.0.2.degree.,
16.0.degree..+-.0.2.degree., 18.7.degree..+-.0.2.degree.,
19.1.degree..+-.0.2.degree., 19.8.degree..+-.0.2.degree.,
22.8.degree..+-.0.2.degree. and 26.8.degree..+-.0.2.degree. degrees
two-theta in an X-ray powder diffraction pattern.
(12) A crystal form of (2) having characteristic infrared
absorption spectra at 1637 cm.sup.1.+-.2 cm.sup.-1, 1536
cm.sup.-1.+-.2 cm.sup.-1, 1501 cm.sup.-1.+-.2 cm.sup.-1 and 1422
cm.sup.-1.+-.2 cm.sup.-1.
(13) A crystal form of (2) having characteristic infrared
absorption spectra at 1637 cm.sup.-1.+-.2 cm.sup.1, 1536
cm.sup.-1.+-.2 cm.sup.-1, 1501 cm.sup.1.+-.2 cm.sup.-1, 1422
cm.sup.-1.+-.2 cm.sup.-1, 1277 cm.sup.-1.+-.2 cm.sup.-1, 1258
cm.sup.-1.+-.2 cm.sup.-1, 1093 cm.sup.-1.+-.2 cm.sup.-1 and 1069
cm.sup.-1.
(14) A crystal form of (2) having one or more spectra selected from
the group consisting of (d) and (e):
(d) X-ray powder diffraction pattern substantially as shown in FIG.
4; and
(e) Infrared absorption spectra substantially as shown in FIG.
5.
(15) A pharmaceutical composition containing the crystal form as
defined in any one of (2) to (14).
(16) A process for preparation of the crystal forms as defined in
any one of (2) to (14).
The present invention features crystalline forms of a salt of
compound of formula AA, in particular a sodium salt.
The present invention features crystalline forms of a hydrate of a
salt of a compound of formula AA, in particular a sodium salt.
This invention also includes a crystal form of a compound of
formula AA (Compound 12, Example 1). Details are shown as (17) to
(22):
(17) A crystal form of a compound of formula AA:
##STR00026##
having one or more physical properties selected from the group
consisting of (v) and (vi): (v) having characteristic diffraction
peaks at 5.4.degree..+-.0.2.degree., 10.7.degree..+-.0.2.degree.,
12.3.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree., and
16.4.degree..+-.0.2.degree. degrees two-theta in an X-ray powder
diffraction pattern; and (vi) having characteristic infrared
absorption spectra at 1658 cm.sup.-1.+-.2 cm.sup.1, 1628
cm.sup.-1.+-.2 cm.sup.-1, 1540 cm.sup.-1.+-.2 cm.sup.-1 and 1498
cm.sup.-1.+-.2 cm.sup.-1.
(18) A crystal form of a compound of formula AA:
##STR00027##
having characteristic diffraction peaks at
5.4.degree..+-.0.2.degree., 10.7.degree..+-.0.2.degree.,
12.3.degree..+-.0.2.degree., 15.2.degree..+-.0.2.degree. and
16.4.degree..+-.0.2.degree. degrees two-theta in an X-ray powder
diffraction pattern.
(19) A crystal form of a compound of formula AA:
##STR00028##
having characteristic diffraction peaks at
5.4.degree..+-.0.2.degree., 10.7.degree..+-.0.2.degree.,
12.3.degree..+-.0.2.degree., 14.3.degree..+-.0.2.degree.,
15.2.degree..+-.0.2.degree., 16.4.degree..+-.0.2.degree.,
21.7.degree..+-.0.2.degree., 24.9.degree..+-.0.2.degree.,
25.4.degree..+-.0.2.degree. and 27.9.degree..+-.0.2.degree. degrees
two-theta in an X-ray powder diffraction pattern.
(20) A crystal of a compound of formula AA:
##STR00029##
having characteristic infrared absorption spectra at 1658
cm.sup.-1.+-.2 cm.sup.-1, 1628 cm.sup.-1.+-.2 cm.sup.-1, 1540
cm.sup.-1.+-.2 cm.sup.-1 and 1498 cm.sup.-1+2 cm.sup.-1.
(21) A crystal of a compound of formula AA:
##STR00030##
having characteristic infrared absorption spectra at 1658
cm.sup.-1.+-.2 cm.sup.-1, 1628 cm.sup.-1.+-.2 cm.sup.-1, 1540
cm.sup.-1.+-.2 cm.sup.-1, 1498 cm.sup.-1.+-.2 cm.sup.-1, 1355
cm.sup.-1.+-.2 cm.sup.-1, 1264 cm.sup.-1.+-.2 cm.sup.-1, 1238
cm.sup.-1.+-.2 cm.sup.-1, 1080 cm.sup.-1.+-.2 cm.sup.-1 and 1056
cm.sup.-1.+-.2 cm.sup.-1.
(22) A crystal of a compound of formula AA:
##STR00031##
having one or, more spectra selected from the group consisting of
(f) and (g):
(f) X-ray powder diffraction pattern substantially as shown in FIG.
6; and
(g) Infrared absorption spectra substantially as shown in FIG.
7.
The crystals of compound 13 and 13b (monohydrate form of compound
13) demonstrate high solubility in water or saline, high
bioavailability (BA), high maximum drug concentration (Cmax), short
maximum drug concentration time (Tmax), high stability against heat
or light, and/or good handling facility. Therefore, the crystals of
compound 13 and 13b are suitable as pharmaceutical ingredients.
In the following examples and throughout this specification, the
following abbreviations may be used: Me (methyl), Bn (benzyl), Aq
(aqueous), Et (ethyl), C (centrigrade).
EXAMPLES
In the following Examples, those depicting the bromination and
amidation reactions of the present invention include Examples C,
Example 2 and Example CC.
The following examples are intended for illustration only and are
not intended to limit the scope of the invention in any way.
Examples 1 and 3
The starting material of Example 1e and 3e is the compound of
formula (IIa) which is also shown as compound 5 below and compound
#101 at page 113 of WO 2006/116764. The product depicted below as
compound 8 is of the formula (I). The final product shown below as
compound 13 is a compound of formula (I-7) at page 240 of WO
2006/116764 wherein (R).sub.m is 2,4-di-F and R.sup.a is H,
provided, however, that there is an alpha methyl at the position
designated R.sup.16 in formula (XXVI) at page 65.
##STR00032## ##STR00033##
Thus, in the above sequence for Example 1, compound 5 is identical
to compound 101 at page 113 of WO 2006/116764 and to formula (IIa)
of the process of the present invention; compound 6 above is
identical to formula (VIa) of the process of the present invention;
compound 7 above is identical to formula (VIb) of the process of
the present invention; and compound 8 is identical to formula (Ia)
of the process of the present invention. Step i) of the invention
process is 5 to 6 above while step ii) is 6 to 8.
Example 1a
To a slurry of 2000 g of compound 1 (1.0 eq.) in 14.0 L of MeCN
were added 2848 g of benzyl bromide (1.05 eq.) and 2630 g of
K.sub.2CO.sub.3 (1.2 eq.). The mixture was stirred at 80.degree. C.
for 5 h and cooled to 13.degree. C. Precipitate was filtered and
washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L
of THF was added to the residue. The THF solution was concentrated
to give 3585 g of crude compound 2 as oil. Without further
purification, compound 2 was used in the next step.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.60 (d, J=5.7 Hz, 1H),
7.4-7.3 (m, 5H), 6.37 (d, J=5.7 Hz, 1H), 5.17 (s, 2H), 2.09 (s,
3H).
Example 1b
To 904 g of the crude compound 2 was added 5.88 L of THF and the
solution was cooled to -60.degree. C. 5.00 L of 1.0 M of Lithium
bis(trimethylsilylamide) in THF (1.25 eq.) was added dropwise for 2
h to the solution of compound 2 at -60.degree. C. Then, a solution
of 509 g of benzaldehyde (1.2 eq.) in 800 mL of THF was added at
-60.degree. C. and the reaction mixture was aged at -60.degree. C.
for 1 h. The THF solution was poured into a mixture of 1.21 L of
conc.HCl, 8.14 L of ice water and 4.52 L of EtOAc at less than
2.degree. C. The organic layer was washed with 2.71 L of brine
(twice) and the aqueous layer was extracted with 3.98 L of EtOAc.
The combined organic layers were concentrated. To the mixture, 1.63
L of toluene was added and concentrated (twice) to provide toluene
slurry of compound 3. Filtration, washing with 0.90 L of cold
toluene and drying afforded 955 g of compound 3 (74% yield from
compound 1) as a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.62 (d, J=5.7 Hz, 1H),
7.5-7.2 (m, 10H), 6.38 (d, J=5.7 Hz, 1H), 5.16 (d, J=11.4 Hz, 1H),
5.09 (d, J=11.4 Hz, 1H), 4.95 (dd, J=4.8, 9.0 Hz, 1H), 3.01 (dd,
J=9.0, 14.1 Hz, 1H), 2.84 (dd, J=4.8, 14.1 Hz, 1H).
Example 1c
To a solution of 882 g of compound 3 (1.0 eq.) in 8.82 L of THF
were added 416 g of Et.sub.3N (1.5 eq.) and 408 g of
methanesulfonyl chloride (1.3 eq.) at less than 30.degree. C. After
confirmation of disappearance of compound 3, 440 mL of NMP and 1167
g of DBU (2.8 eq.) were added to the reaction mixture at less than
30.degree. C. and the reaction mixture was aged for 30 min. The
mixture was neutralized with 1.76 L of 16% sulfuric acid and the
organic layer was washed with 1.76 L of 2% Na.sub.2SO.sub.3 aq.
After concentration of the organic layer, 4.41 L of toluene was
added and the mixture was concentrated (tree times). After addition
of 4.67 L of hexane, the mixture was cooled with ice bath.
Filtration, washing with 1.77 L of hexane and drying provided 780 g
of compound 4 (94% yield) as a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.69 (d, J=5.7 Hz, 1H),
7.50-7.25 (m, 10H), 7.22 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.2 Hz,
1H), 6.41 (d, J=5.7 Hz, 1H), 5.27 (s, 2H).
Example 1d
To a mixture of 822 g of compound 4 (1.0 eq.) and 11.2 g of
RuCl.sub.3.nH.sub.2O (0.02 eq.) in 2.47 L of MeCN, 2.47 L of EtOAc
and 2.47 L of H.sub.2O was added 2310 g of NaIO.sub.4 (4.0 eq.) at
less than 25.degree. C. After aging for 1 h, 733 g of NaClO.sub.2
(3.0 eq.) was added to the mixture at less than 25.degree. C. After
aging for 1 h, precipitate was filtered and washed with 8.22 L of
EtOAc. To the filtrate, 1.64 L of 50% Na.sub.2S.sub.2O.sub.3 aq,
822 mL of H.sub.2O and 630 mL of coc.HCl were added. The aqueous
layer was extracted with 4.11 L of EtOAc and the organic layers
were combined and concentrated. To the residue, 4 L of toluene was
added and the mixture was concentrated and cooled with ice bath.
Filtration, washing with 1 L of toluene and drying provided 372 g
of compound 5 (56% yield) as a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.78 (d, J=5.7 Hz, 1H),
7.54-7.46 (m, 2H), 7.40-7.26 (m, 3H), 6.48 (d, J=5.7 Hz, 1H), 5.6
(brs, 1H), 5.31 (s, 2H).
Example 1e
A mixture of 509 g of compound 5 (1.0 eq.) and 407 g of
3-amino-propane-1,2-diol (2.5 eq.) in 1.53 L of EtOH was stirred at
65.degree. C. for 1 h and at 80.degree. C. for 6 h. After addition
of 18.8 g of 3-Amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH,
the mixture was stirred at 80.degree. C. for 1 h. After addition of
18.8 g of 3-amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH, the
mixture was stirred at 80.degree. C. for 30 min. After cooling and
addition of 509 mL of H.sub.2O, the mixture was concentrated. To
the residue, 2.54 L of H.sub.2O and 2.54 L of AcOEt were added.
After separation, the aqueous layer was washed with 1.02 L of
EtOAc. To the aqueous layer, 2.03 L of 12% sulfuric acid was added
at less than 12.degree. C. to give crystal of compound 6.
Filtration, washing with 1.53 L of cold H.sub.2O and drying
provided 576 g of compound 6 (83% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.67 (d, J=7.5 Hz, 1H),
7.5-7.2 (m, 5H), 6.40 (d, J=7.5 Hz, 1H), 5.07 (s, 2H), 4.2-4.0 (m,
1H), 3.9-3.6 (m, 2H), 3.38 (dd, J=4.2, 10.8 Hz, 1H), 3.27 (dd,
J=6.0, 10.8 Hz, 1H).
Example 1f
To a slurry of 576 g of compound 6 (1.0 eq.: 5.8% of H.sub.2O was
contained) in 2.88 L of NMP were added 431 g of NaHCO.sub.3 (3.0
eq.) and 160 mL of methyl iodide (1.5 eq.) and the mixture was
stirred at room temperature for 4 h. After cooling to 5.degree. C.,
1.71 L of 2N HCl and 1.15 L of 20% NaClaq were added to the mixture
at less than 10.degree. C. to give crystal of compound 7.
Filtration, washing with 1.73 L of H.sub.2O and drying provided 507
g of compound 7 (89% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.59 (d, J=7.5 Hz, 1H),
7.40-7.28 (m, 5H), 6.28 (d, J=7.5 Hz, 1H), 5.21 (d, J=5.4 Hz, 1H),
5.12 (d, J=10.8 Hz, 1H), 5.07 (d, J=10.8 Hz, 1H), 4.83 (t, J=5.7
Hz, 1H), 3.97 (dd, J=2.4, 14.1 Hz, 1H), 3.79 (s, 3H), 3.70 (dd,
J=9.0, 14.4 Hz, 1H), 3.65-3.50 (m, 1H), 3.40-3.28 (m, 1H),
3.26-3.14 (m, 1H).
Example 1g
To a mixture of 507 g of compound 7 (1.0 eq.) in 5.07 L of MeCN,
5.07 L of H.sub.2O and 9.13 g of AcOH (0.1 eq.) was added 390 g of
NaIO.sub.4 (1.2 eq.) and the mixture was stirred at room
temperature for 2 h. After addition of 1.52 L of 10%
Na.sub.2S.sub.2O.sub.3 aq., the mixture was concentrated and cooled
to 10.degree. C. Filtration, washing with H.sub.2O and drying
provided 386 g of compound 8 (80% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.62 (d, J=7.5 Hz, 1H),
7.42-7.30 (m, 5H), 6.33 (d, J=6.0 Hz, 2H), 6.29 (d, J=7.5 Hz, 1H),
5.08 (s, 2H), 4.95-4.85 (m, 1H), 3.80 (s, 3H), 3.74 (d, J=5.1 Hz,
2H).
Example 1h
After dissolution of a mixture of 378 g of compound 8 (1.0 eq.) in
3.78 L of MeOH by heating, the solution was concentrated. To the
residue, 1.51 L of toluene was added and the mixture was
concentrated. To the residue, 1.89 L of toluene, 378 mL of AcOH and
137 g of (R)-3-Amino-butan-1-ol (1.3 eq.) were added and the
mixture was heated to 90.degree. C., stirred at 90.degree. C. for
2.5 h and concentrated. To the residue, 1.89 L of toluene was added
and the mixture was concentrated. The residue was extracted with
3.78 L and 1.89 L of CHCl.sub.3 and washed with 2.times.1.89 L of
H.sub.2O. The organic layers were combined and concentrated. To the
residue, 1.89 L of EtOAc was added and the mixture was
concentrated. After addition of 1.89 L of EtOAc, filtration,
washing with 1.13 L of EtOAc and drying provided 335 g of compound
9 (83% yield) as a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.70-7.58 (m, 2H),
7.40-7.24 (m, 3H), 7.14 (d, J=7.5 Hz, 2H), 6.47 (d, J=7.5 Hz, 1H),
5.35 (d, J=10.2 Hz, 1H), 5.28 (d, J=10.2 Hz, 1H), 5.12 (dd, J=3.9,
6.3 Hz, 1H), 5.05-4.90 (m, 1H), 4.07 (dd, J=3.9, 13.5 Hz, 1H),
4.00-3.86 (m, 3H), 2.23-2.06 (m, 1H), 1.48 (ddd, J=2.4, 4.5, 13.8
Hz, 1H), 1.30 (d, J=6.9 Hz, 3H).
Example 1i
To a slurry of 332 g of compound 9 (1.0 eq.) in 1.66 L of NMP was
added 191 g of NBS (1.1 eq.) and the mixture was stirred at room
temperature for 2 h. After addition of 1.26 L of H.sub.2O, the
mixture was stirred for 30 min. After addition of 5.38 L of
H.sub.2O and aging of the mixture at 10.degree. C. for 30 min and
at 5.degree. C. for 1 h, filtration, washing with 1.33 L of cold
H.sub.2O and drying provided 362 g of compound 10 (89% yield) as a
crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.69-7.63 (m, 2H), 7.59
(s, 1H), 7.38-7.24 (m, 3H), 5.33 (d, J=10.2 Hz, 1H), 5.25 (d, J=9.9
Hz, 1H), 5.12 (dd, J=3.9, 5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.11 (dd,
J=3.9, 13.2 Hz, 1H), 4.02-3.88 (m, 3H), 2.21-2.06 (m, 1H), 1.49
(ddd, J=2.4, 4.5, 14.1 Hz, 1H), 1.31 (d, J=6.9 Hz, 3H).
Example 1j
Under carbon mono-oxide atmosphere, a mixture of 33.5 g of compound
10 (1.0 eq.), 34.8 mL of i-Pr.sub.2NEt (2.5 eq.), 14.3 mL of
2,4-difluorobenzylamine (1.5 eq.) and 4.62 g of Pd(PPh.sub.3).sub.4
(0.05 eq.) in 335 mL of DMSO was stirred at 90.degree. C. for 5.5
h. After cooling, precipitate was filtered and washed with 50 mL of
2-propanol. After addition of 502 mL of H.sub.2O and 670 mL of
AcOEt to the filtrate, the organic layer was washed with 335 mL of
0.5N HClaq. and 335 mL of H.sub.2O and the aqueous layer was
extracted with 335 mL of AcOEt. The organic layers were combined
and concentrated. To the residue, 150 mL of 2-propanol was added
and the mixture was concentrated. After addition of 150 mL of
2-propanol, concentration, cooling to 20.degree. C. and filtration,
crude crystal of compound 11 was obtained. After dissolution of the
crude crystal in 380 mL of acetone by heating, precipitate was
filtered and the filtrate was concentrated. After addition of 200
mL of EtOH, concentration, addition of 150 mL of EtOH,
concentration, cooling and filtration, crude crystal of compound 11
was obtained. After dissolution of the crude crystal in 450 mL of
acetone by heating, the solution was concentrated. To the residue,
150 mL of 2-propanol was added and the mixture was concentrated
(twice). After cooling of the residue, filtration, washing with
2-propanol and drying provided 34.3 g of compound 11 (84% yield) as
a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.40 (t, J=6.0 Hz, 1H),
8.35 (s, 1H), 7.66-7.58 (m, 2H), 7.42-7.24 (m, 5H), 6.78-6.74 (m,
2H), 5.30 (d, J=9.9 Hz, 1H), 5.26 (d, J=10.2 Hz, 1H), 5.15 (dd,
J=3.9, 5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.64 (d, J=5.4 Hz, 2H), 4.22
(dd, J=3.9, 13.5, 1H), 4.09 (dd, J=6.0, 13.2 Hz, 1H), 4.02-3.88 (m,
2H), 2.24-1.86 (m, 1H), 1.50 (ddd, J=2.4, 4.5, 14.1 Hz, 1H), 1.33
(d, J=7.2 Hz, 3H).
Example 1k
Under hydrogen atmosphere, a mixture of 28.0 g of compound 11 (1.0
eq.) and 5.6 g of 10% Pd--C in 252 mL of THF and 28 mL of MeOH was
stirred for 1 h. After precipitate (Pd--C) was filtered and washed
with 45 mL of THF, 5.6 g of 10% Pd--C was added and the mixture was
stirred for 1.5 h under hydrogen atmosphere. After Pd--C was
filtered and washed with 150 mL of CHCl.sub.3/MeOH (9/1), the
filtrate was concentrated. After dissolution of the residue in 1.38
L of EtOH by heating, the solution was gradually cooled to room
temperature. After filtration, the filtrate was concentrated and
cooled. Filtration, washing with EtOH and drying provided 21.2 g of
compound 12 (92% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.51 (s, 1H), 10.36
(t, J=5.7 Hz, 1H), 8.50 (s, 1H), 7.39 (td, J=8.7, 6.3 Hz, 1H), 7.24
(ddd, J=2.6, 9.5, 10.8 Hz, 1H), 7.12-7.00 (m, 1H), 5.44 (dd, J=3.9,
5.7 Hz, 1H), 4.90-4.70 (m, 1H), 4.65-4.50 (m, 1H), 4.54 (d, J=5.1
Hz, 2H), 4.35 (dd, J=6.0, 13.8 Hz, 1H), 4.10-3.98 (m, 1H),
3.96-3.86 (m, 1H), 2.10-1.94 (m, 1H), 1.60-1.48 (m, 1H), 1.33 (d,
J=6.9 Hz, 3H).
Example 1l
After dissolution of 18.0 g of compound 12 (1.0 eq.) in 54 mL of
EtOH by heating, followed by filtration, 21.5 mL of 2N NaOHaq. (1.0
eq.) was added to the solution at 80.degree. C. The solution was
gradually cooled to room temperature. Filtration, washing with 80
mL of EtOH and drying provided. 18.8 g of compound 13 (99% yield)
as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.70 (t, J=6.0 Hz,
1H), 7.89 (s, 1H), 7.40-7.30 (m, 1H), 7:25-7.16 (m, 1H), 7.06-6.98
(m, 1H), 5.22-5.12 (m, 1H), 4.87-4.74 (m, 1H), 4.51 (d, J=5.4 Hz,
2H), 4.35-4.25 (m, 1H), 4.16 (dd, J=1.8, 14.1 Hz, 1H), 4.05-3.90
(m, 1H), 3.86-3.74 (m, 1H), 2.00-1.72 (m, 1H), 1.44-1.32 (m, 1H),
1.24 (d, J=6.9 Hz, 3H).
Example 1m
Example 1m shows a process for preparation of the crystalline
compound 13b which is monohydrate form of compound 13.
After dissolution of 30.0 g of compound 13 (1.0 eq.) in 600 mL of
THF-water solution (8:2) by 30.degree. C., 36.0 mL of 2N NaOHaq
(1.0 eq.) was added to the solution. The mixture was stirred at
room temperature for 2 hours. The precipitation was filtered,
washing with 150 mL of TI-IF-water solution (8:2), 150 mL of THF.
Drying at 85.degree. C. and humidity conditioning provided 30.4 g
of compound 13b (monohydrate form of compound 13, 93% yield) as a
crystal.
Example 3
Example 3a
To a slurry of 2000 g of compound 1 (1.0 eq.) in 14.0 L of MeCN
were added 2848 g of benzyl bromide (1.05 eq.) and 2630 g of
K.sub.2CO.sub.3 (1.2 eq.). The mixture was stirred at 80.degree. C.
for 5 h and cooled to 13.degree. C. Precipitate was filtered and
washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L
of THF was added to the residue. The THF solution was concentrated
to give 3585 g of crude compound 2 as oil. Without further
purification, compound 2 was used in the next step.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.60 (d, J=5.7 Hz, 1H),
7.4-7.3 (m, 5H), 6.37 (d, J=5.7 Hz, 1H), 5.17 (s, 2H), 2.09 (s,
3H).
Example 3b
To 904 g of the crude compound 2 was added 5.88 L of THF and the
solution was cooled to -60.degree. C. 5.00 L of 1.0 M of Lithium
bis(trimethylsilylamide) in THF (1.25 eq.) was added dropwise for 2
h to the solution of compound 2 at -60.degree. C. Then, a solution
of 509 g of benzaldehyde (1.2 eq.) in 800 mL of THF was added at
-60.degree. C. and the reaction mixture was aged at -60.degree. C.
for 1 h. The THF solution was poured into a mixture of 1.21 L of
conc.HCl, 8.14 L of ice water and 4.52 L of EtOAc at less than
2.degree. C. The organic layer was washed with 2.71 L of brine
(twice) and the aqueous layer was extracted with 3.98 L of EtOAc.
The combined organic layers were concentrated. To the mixture, 1.63
L of toluene was added and concentrated (twice) to provide toluene
slurry of compound 3. Filtration, washing with 0.90 L of cold
toluene and drying afforded 955 g of compound 3 (74% yield from
compound 1) as a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.62 (d, J=5.7 Hz, 1H),
7.5-7.2 (m, 10H), 6.38 (d, J=5.7 Hz, 1H), 5.16 (d, J=11.4 Hz, 1H),
5.09 (d, J=11.4 Hz, 1H), 4.95 (dd, J=4.8, 9.0 Hz, 1H), 3.01 (dd,
J=9.0, 14.1 Hz, 1H), 2.84 (dd, J=4.8, 14.1 Hz, 1H).
Example 3c
To a solution of 882 g of compound 3 (1.0 eq.) in 8.82 L of THF
were added 416 g of Et.sub.3N (1.5 eq.) and 408 g of
methanesulfonyl chloride (1.3 eq.) at less than 30.degree. C. After
confirmation of disappearance of compound 3, 440 mL of NMP and 1167
g of DBU (2.8 eq.) were added to the reaction mixture at less than
30.degree. C. and the reaction mixture was aged for 30 min. The
mixture was neutralized with 1.76 L of 16% sulfuric acid and the
organic layer was washed with 1.76 L of 2% Na.sub.2SO.sub.3 aq.
After concentration of the organic layer, 4.41 L of toluene was
added and the mixture was concentrated (tree times). After addition
of 4.67 L of hexane, the mixture was cooled with ice bath.
Filtration, washing with 1.77 L of hexane and drying provided 780 g
of compound 4 (94% yield) as a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.69 (d, J=5.7 Hz, 1H),
7.50-7.25 (m, 10H), 7.22 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.2 Hz,
1H), 6.41 (d, J=5.7 Hz, 1H), 5.27 (s, 2H).
Example 3d
To a mixture of 10.0 g of compound 4 and 13.6 mg of
RuCl.sub.3.nH.sub.2O in 95 mL of MeCN and 10 mL of water, mixture
of 155 mL of water, 7.2 g of hydrosulfuric acid, and 15.5 g of
NaIO.sub.4 was added for 2.5 h at 20.degree. C. After aging for 1
h, organic and aqueous layers were separated and aqueous layer was
exracted by 30 mL of ethyl acetate. Aqueous layer was exracted
again by 30 mL of ethyl acetate and organic layers were combined. 6
mL of 5% NaHSO.sub.3 solution was added to the combined organic
layer and the layers were separated. The organic layer was adjusted
to pH 6.0 by adding 4.0 g of 2M NaOH solution and the aqueous layer
was separated. After 60 mL of 5% NaHCO.sub.3 solution and 257 mg of
TEMPO was added, 25.9 g of NaClO solution was added to the reaction
mixture at 25.degree. C. for 1 h and stirred for 30 min to check
the reaction was finished. After the layers were separated, 42.5 mL
of 5% Na2SO3 solution and 30 mL of AcOEt were added and separated.
The aqueous layer was exracted by 30 mL of AcOEt and separated. 12%
H.sub.2SO.sub.4 was added to the reaction mixture at 20.degree. C.
for 1 h and the mixture was cooled to 5.degree. C. After the
mixture was stirred for 30 min, the mixture was filtered, washed
with 30 mL of water twice and dryed to provide 5.7 g of compound 5
(70% yield) as a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.78 (d, J=5.7 Hz, 1H),
7.54-7.46 (m, 2H), 7.40-7.26 (m, 3H), 6.48 (d, J=5.7 Hz, 1H), 5.6
(brs, 1H), 5.31 (s, 2H).
Example 3e
A mixture of 509 g of compound 5 (1.0 eq.) and 407 g of
3-amino-propane-1,2-diol (2.5 eq.) in 1.53 L of EtOH was stirred at
65.degree. C. for 1 h and at 80.degree. C. for 6 h. After addition
of 18.8 g of 3-Amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH,
the mixture was stirred at 80.degree. C. for 1 h. After addition of
18.8 g of 3-amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH, the
mixture was stirred at 80.degree. C. for 30 min. After cooling and
addition of 509 mL of H.sub.2O, the mixture was concentrated. To
the residue, 2.54 L of H.sub.2O and 2.54 L of AcOEt were added.
After separation, the aqueous layer was washed with 1.02 L of
EtOAc. To the aqueous layer, 2.03 L of 12% sulfuric acid was added
at less than 12.degree. C. to give crystal of compound 6.
Filtration, washing with 1.53 L of cold H.sub.2O and drying
provided 576 g of compound 6 (83% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.67 (d, J=7.5 Hz, 1H),
7.5-7.2 (m, 5H), 6.40 (d, J=7.5 Hz, 1H), 5.07 (s, 2H), 4.2-4.0 (m,
1H), 3.9-3.6 (m, 2H), 3.38 (dd, J=4.2, 10.8 Hz, 1H), 3.27 (dd,
J=6.0, 10.8 Hz, 1H).
Example 3f
To a slurry of 576 g of compound 6 (1.0 eq.: 5.8% of H.sub.2O was
contained) in 2.88 L of NMP were added 431 g of NaHCO.sub.3 (3.0
eq.) and 160 mL of methyl iodide (1.5 eq.) and the mixture was
stirred at room temperature for 4 h. After cooling to 5.degree. C.,
1.71 L of 2N HCl and 1.15 L of 20% NaClaq were added to the mixture
at less than 10.degree. C. to give crystal of compound 7.
Filtration, washing with 1.73 L of H.sub.2O and drying provided 507
g of compound 7 (89% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.59 (d, J=7.5 Hz, 1H),
7.40-7.28 (m, 5H), 6.28 (d, J=7.5 Hz, 1H), 5.21 (d, J=5.4 Hz, 1H),
5.12 (d, J=10.8 Hz, 1H), 5.07 (d, J=10.8 Hz, 1H), 4.83 (t, J=5.7
Hz, 1H), 3.97 (dd, J=2.4, 14.1 Hz, 1H), 3.79 (s, 3H), 3.70 (dd,
J=9.0, 14.4 Hz, 1H), 3.65-3.50 (m, 1H), 3.40-3.28 (m, 1H),
3.26-3.14 (m, 1H).
Example 3g
To a mixture of 15.0 g of compound 7 (1.0 eq.) in 70.9 g of MeCN, a
mixture of 60 mL of H.sub.2O, 2.6 g of H.sub.2SO.sub.4 and 11.5 g
of NaIO.sub.4 was added in the range between 17.degree. C. to
14.degree. C. After the reaction mixture was stirred for 1 hour,
precipitate was filtered. The filterate was added to the solution
of 11.8 g of ascorbic acid sodium salt, 64 g of water and 60 mg of
H.sub.2SO.sub.4. After the mixture was concentrated, cooling to
5.degree. C., filtration, washing with H.sub.2O and drying provided
12.9 g of compound 8 (90% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.62 (d, J=7.5 Hz, 1H),
7.42-7.30 (m, 5H), 6.33 (d, J=6.0 Hz, 2H), 6.29 (d, J=7.5 Hz, 1H),
5.08 (s, 2H), 4.95-4.85 (m, 1H), 3.80 (s, 3H), 3.74 (d, J=5.1 Hz,
2H).
Example 3h
A mixture of 10.0 g of compound 8 and 33.3 g of diglyme were added
the solution of 3.3 g of (R)-3-Amino-butan-1-ol in 4.7 g of diglyme
and 1.0 g of acetic acid at 60.degree. C. After the reaction
mixture was stirred at 95.degree. C. for 9 hours, the reaction
mixture was cooled to -5.degree. C. and filtered. The wet crystal
was washed and dryed to give 8.3 g of compound 9 (78%). XRD
data:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.70-7.58 (m, 2H),
7.40-7.24 (m, 3H), 7.14 (d, J=7.5 Hz, 2H), 6.47 (d, J=7.5 Hz, 1H),
5.35 (d, J=10.2 Hz, 1H), 5.28 (d, J=10.2 Hz, 1H), 5.12 (dd, J=3.9,
6.3 Hz, 1H), 5.05-4.90 (m, 1H), 4.07 (dd, J=3.9, 13.5 Hz, 1H),
4.00-3.86 (m, 3H), 2.23-2.06 (m, 1H), 1.48 (ddd, J=2.4, 4.5, 13.8
Hz, 1H), 1.30 (d, J=6.9 Hz, 3H).
Example 3i
To slurry of 5.7 g of NBS in 26.5 g of dichloromethane was added 10
g of compound 9 in 92.8 g of dichloromethane at room temperature.
After thr reaction mixture was stirred for 6.5 h, the reaction
mixture was added to the solution of 2.0 g Na2SO3 and 40.3 g of
water. The organic layer was washed with diluted NaOH solution and
water, dichloromethane was concentrated and was displaced by
methanol. The mixture was cooled to -5.degree. C. and filtered and
the wet crystal was washed and dryed to give 10.3 g of compound 10
(84%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.69-7.63 (m, 2H), 7.59
(s, 1H), 7.38-7.24 (m, 3H), 5.33 (d, J=10.2 Hz, 1H), 5.25 (d, J=9.9
Hz, 1H), 5.12 (dd, J=3.9, 5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.11 (dd,
J=3.9, 13.2 Hz, 1H), 4.02-3.88 (m, 3H), 2.21-2.06 (m, 1H), 1.49
(ddd, J=2.4, 4.5, 14.1 Hz, 1H), 1.31 (d, J=6.9 Hz, 3H).
Example 3j
Under carbon mono-oxide atmosphere, a mixture of 25.0 g of compound
10, 11.6 g of i-Pr.sub.2NEt, 12.8 g of 2,4-difluorobenzylamine; 335
mg of Pd(OAc).sub.2 and 1.9 g of 1,4-bis(diphenylphosphino)butane
in 188 mL of DMA was stirred at 85.degree. C. for 4 h. After
cooling, the reaction mixture was devided and 10/25 of mixture was
used for next step. 6.6 g of AcOEt, 29.9 g of water and 3 mg of
seed crystal were added to the reaction mixture at 40.degree. C.
After stirring for 7 min, 29.9 g of water was added and cooled to
room temperature. The crystal was filtered at room temperature and
washed by 47.2 g of ethanol to give 10.1 g of compound 11 (83%
yield) as a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.40 (t, J=6.0 Hz, 1H),
8.35 (s, 1H), 7.66-7.58 (m, 2H), 7.42-7.24 (m, 5H), 6.78-6.74 (m,
2H), 5.30 (d, J=9.9 Hz, 1H), 5.26 (d, J=10.2 Hz, 1H), 5.15 (dd,
J=3.9, 5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.64 (d, J=5.4 Hz, 2H), 4.22
(dd, J=3.9, 13.5, 1H), 4.09 (dd, J=6.0, 13.2 Hz, 1H), 4.02-3.88 (m,
2H), 2.24-1.86 (m, 1H), 1.50 (ddd, J=2.4, 4.5, 14.1 Hz, 1H), 1.33
(d, J=7.2 Hz, 3H).
Example 3k
Under hydrogen atmosphere, a mixture of 4.0 g of compound 11 and
0.8 g of 50% wet 5% Pd--C in 67.6 mL of THF and 1.6 mL of H.sub.2O
was stirred for 1.5 h at 50.degree. C. After mixture of 80 mg of
NaHSO.sub.3 and 2.0 mL of purified water was added to the reaction
mixture and the reaction mixture was stirred for 1 h, precipitate
was filtered, washed with 20 mL of THF, and the filtrate was
concentrated to 11.97 g. After adding 6.7 mL of ethanol and 33.6 mL
of purified water over 1 h, reaction mixture was cooled to
25.degree. C. Filtration, washing with 26.9 mL of EtOH and drying
provided 2.33 g of compound 12 (82% yield) as a. crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.51 (s, 1H), 10.36
(t, J=5.7 Hz, 1H), 8.50 (s, 1H), 7.39 (td, J=8.7, 6.3 Hz, 1H), 7.24
(ddd, J=2.6, 9.5, 10.8 Hz, 1H), 7.12-7.00 (m, 1H), 5.44 (dd, J=3.9,
5.7 Hz, 1H), 4.90-4.70 (m, 1H), 4.65-4.50 (m, 1H), 4.54 (d, J=5.1
Hz, 2H), 4.35 (dd, J=6.0, 13.8 Hz, 1H), 4.10-3.98 (m, 1H),
3.96-3.86 (m, 1H), 2.10-1.94 (m, 1H), 1.60-1.48 (m, 1H), 1.33 (d,
J=6.9 Hz, 3H).
Example 3l
After dissolution of 18.0 g of compound 12 (1.0 eq.) in 54 mL of
EtOH by heating, followed by filtration, 21.5 mL of 2N NaOHaq. (1.0
eq.) was added to the solution at 80.degree. C. The solution was
gradually cooled to room temperature. Filtration, washing with 80
mL of EtOH and drying provided 18.8 g of compound 13 (99% yield) as
a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.70 (t, J=6.0 Hz,
1H), 7.89 (s, 1H), 7.40-7.30 (m, 1H), 7.25-7.16 (m, 1H), 7.06-6.98
(m, 1H), 5.22-5.12 (m, 1H), 4.87-4.74 (m, 1H), 4.51 (d, J=5.4 Hz,
2H), 4.35-4.25 (m, 1H), 4.16 (dd, J=1.8, 14.1 Hz, 1H), 4.05-3.90
(m, 1H), 3.86-3.74 (m, 1H), 2.00-1.72 (m, 1H), 1.44-1.32 (m, 1H),
1.24 (d, J=6.9 Hz, 3H).
Apparatus and conditions used to generate FIGS. 1-7 are as
follows:
Measurement of X-ray Powder Diffraction Pattern
The measuring conditions used were the same as general metrology
for the X-ray powder diffraction pattern measurement described in
"The Japanese Pharmacopoeia Fifteenth Edition".
Measuring Apparatus
RINT TTR III
Methods
The acquisition conditions were as follows.
Measurement Method: parallel beam method
Tube anode: Cu
Radiation: Cu K.alpha.
Generator current: 300 mA
Generator tension: 50 kV
The sample was prepared on an aluminum wafer
Angle of incidence: 4.degree. and 40.degree.
Measurement of Infrared Spectroscopy Analysis
The acquisition conditions used for were as follows.
Measuring Apparatus
FT/1R-4200 typeA (by JASCO Corporation)
Methods
Measurement method: ATR (Attenuated total reflection) method
Resolution: 4 (cm-1)
Detector: DLATGS
Accumulation: 32 times
Measurement of Solid-State .sup.13C NMR Spectra
The spectrum was obtained using the cross polarization
magic-angle-spinning (CP/MAS) method. The acquisition conditions
were as follows.
Measuring Apparatus
Spectrometer: Varian NMR Systems (1H frequency: 599.8 MHz)
Methods
Probe: 3.2 mm T3 HX Probe
Spectral width: 43103.4 Hz
Acquisition Time: 0.04s
Recycle Delay: 10s
Contact Time: 3 ms
External standard: adamantane (methyne carbon:38.52 ppm)
Temperature: 10
MAS rate: 20 kHz
Example A
The starting material of Example A is compound 8, which is
identical to formula (Ia). Thus, Example A depicts a process in
providing an intermediate for the compound of formula 17 below
which is isomeric to the compound ZZ-2 at page 237 of WO
2006/116764 to Brian Johns et al.
##STR00034##
Example Aa
After dissolution of mixture of 320 g of compound 8 (1.0 eq.) in
3.20 L of MeOH by heating, the solution was concentrated. To the
residue, 1.66 L of MeCN, 5.72 mL of AcOH (0.1 eq.) and 82.6 g of
(S)-2-Amino-propan-1-ol (1.1 eq.) were added and the mixture was
heated to 70.degree. C., stirred at 70.degree. C. for 4 h and
concentrated. To the residue, 1.67 L of 2-propanol was added and
the mixture was concentrated (twice). After cooling of the residue,
filtration, washing with 500 mL of cold 2-propanol and drying
provided 167 g of compound 14 (52% yield) as a crystal.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.61-7.55 (m, 2H),
7.40-7.20 (m, 4H), 6.53 (d, J=7.2, 1H), 5.46 (d, J=10.5 Hz, 1H),
5.23 (d, J=10.2 Hz, 1H), 5.20 (dd, J=3.9, 9.6 Hz, 1H), 4.46-4.34
(m, 1H), 4.31 (dd, J=6.6, 8.7 Hz, 1H), 4.14 (dd, J=3.9, 12.3 Hz,
1H), 3.79 (dd, J=9.9, 12.3 Hz, 1H), 3.62 (dd, J=6.9, 8.7 Hz, 1H),
1.38 (d, J=6.3 Hz, 3H).
Example Ab
To slurry of 156 g of compound 14 (1.0 eq.) in 780 mL of NMP was
added 93.6 g of NBS (1.1 eq.) and the mixture was stirred at room
temperature for 2.5 h. The reaction mixture was added to 3.12 L of
H.sub.2O. Filtration, washing with 8.0 L of H.sub.2O and drying
provided 163 g of compound 15 (84% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.37 (s, 1H), 7.55-7.50
(m, 2H), 7.42-7.25 (m, 3H), 5.34 (dd, J=3.6, 9.9 Hz, 1H), 5.18 (d,
J=10.8 Hz, 1H), 5.03 (d, J=10.5 Hz, 1H), 4.53 (dd, J=3.6, 12.0 Hz,
1H), 4.40-4.20 (m, 2H), 3.99 (dd, J=9.9, 11.7 Hz, 1H), 3.64 (dd,
J=5.7, 8.1 Hz, 1H), 1.27 (d, J=6.3 Hz, 3H).
Example Ac
Under carbon mono-oxide atmosphere, a mixture of 163 g of compound
15 (1.0 eq.), 163 mL of i-Pr.sub.2NEt (2.5 eq.), 68.4 mL of
2,4-difluorobenzylamine (1.5 eq.) and 22.5 g of Pd(PPh.sub.3).sub.4
(0.05 eq.) in 816 mL of DMSO was stirred at 90.degree. C. for 7 h.
After cooling, removal of precipitate, washing with 50 mL of DMSO
and addition of 11.3 g of Pd(PPh.sub.3).sub.4 (0.025 eq.), the
reaction mixture was stirred at 90.degree. C. for 2 h under carbon
mono-oxide atmosphere again. After cooling, removal of precipitate
and addition of 2.0 L of AcOEt and 2.0 L of H.sub.2O, the organic
layer was washed with 1.0 L of 1N HClaq. and 1.0 L of H.sub.2O
(twice) and the aqueous layer was extracted with 1.0 L of AcOEt.
The organic layers were combined and concentrated. Silica gel
column chromatography of the residue provided 184 g of compound 16
(96% yield) as foam.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.38 (t, J=6.3 Hz, 1H),
8.39 (s, 1H), 7.75-7.25 (m, 7H), 6.90-6.70 (m, 2H), 5.43 (d, J=10.2
Hz, 1H), 5.24 (d, J=10.2 Hz, 1H), 5.19 (dd, J=3.9, 9.9 Hz, 1H),
4.63 (d, J=6.0 Hz, 2H), 4.50-4.25 (m, 3H), 3.86 (dd, J=9.9, 12.3
Hz, 1H), 3.66 (dd, J=6.9, 8.4 Hz, 1H), 1.39 (d, J=6.0 Hz, 3H).
Example Ad
Under hydrogen atmosphere, a mixture of 184 g of compound 16 (1.0
eq.) and 36.8 g of 10% Pd--C in 3.31 L of THF and 0.37 L of MeOH
was stirred for 3 h. After filtration of precipitate (Pd--C),
washing with THF/MeOH (9/1) and addition of 36.8 g of 10% Pd--C,
the mixture was stirred for 20 min under hydrogen atmosphere. After
filtration of precipitate (Pd--C) and washing with THF/MeOH (9/1),
the filtrate was concentrated. After 200 mL of AcOEt was added to
the residue, filtration afforded crude solid of compound 17. The
precipitates were combined and extracted with 4.0 L of
CHCl.sub.3/MeOH (5/1). After concentration of the CHCl.sub.3/MeOH
solution and addition of 250 mL of AcOEt to the residue, filtration
afforded crude solid of compound 17. The crude solids were combined
and dissolved in 8.2 L of MeCN/H.sub.2O (9/1) by heating. After
filtration, the filtrate was concentrated. To the residue, 1.5 L of
EtOH was added and the mixture was concentrated (three times).
After cooling of the residue, filtration and drying provided 132 g
of compound 17 (88% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.47 (brs, 1H), 10.31
(t, J=6.0 Hz, 1H), 8.46 (s, 1H), 7.40 (td, J=8.6, 6.9 Hz, 1H), 7.24
(ddd, J=2.6, 9.4, 10.6, 1H), 7.11-7.01 (m, 1H), 5.39 (dd, J=4.1,
10.4 Hz, 1H), 4.89 (dd, J=4.2, 12.3 Hz, 1H), 4.55 (d, J=6.0 Hz,
2H), 4.40 (dd, J=6.8, 8.6 Hz, 1H), 4.36-4.22 (m, 1H), 4.00 (dd,
J=10.2, 12.3. Hz, 1H), 3.67 (dd, J=6.7, 8.6 Hz, 1H), 1.34 (d, J=6.3
Hz, 3H).
Example Ae
After dissolution of 16.0 g of compound 17 (1.0 eq.) in 2.56 L of
EtOH and 0.64 L of H.sub.2O by heating, followed by filtration, 39
mL of 1N NaOHaq. (1.0 eq.) was added to the solution at 75.degree.
C. The solution was gradually cooled to room temperature.
Filtration, washing with 80 mL of EtOH and drying provided 13.5 g
of compound 18 (80% yield) as a crystal.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.73 (t, J=6.0 Hz,
1H), 7.89 (s, 1H), 7.40-7.30 (m, 1H), 7.25-7.16 (m, 1H), 7.07-6.98
(m, 1H), 5.21 (dd, J=3.8, 10.0 Hz, 1H), 4.58 (dd, J=3.8, 12.1 Hz,
1H), 4.51 (d, J=5.4 Hz, 2H), 4.30-4.20 (m, 2H), 3.75 (dd, J=10.0,
12.1 Hz, 1H), 3.65-3.55 (m, 1H), 1.27 (d, J=6.1 Hz, 3H).
Example B
This Example B utilizes a process to insert a ring nitrogen in
place of oxygen in a pyrone ring and create an aldehyde equivalent
by an osmium oxidation of a double bond. Thus, this example is not
a bromination of the invention.
##STR00035##
Example Ba
To a bromobenzene (238 ml) solution of compound A (23.8 g, 110
mmol), selene dioxide (24.4 g, 220 mmol) was added. The reaction
mixture was stirred for 13 hours at 140.degree. C. with removing
water by Dean-Stark trap. Insoluble particles were removed by
filtration after cooling, and solvent was evaporated. Toluene was
added to the residue and precipitates were filtered off. After
concentration in vaccuo, the residue was purified by silica gel
column chromatography (hexane/ethyl acetate). Compound B (16.5 g,
65%) was obtained as yellow oil.
.sup.1H-NMR (CDCl.sub.3) .delta.: 5.51 (2H, s), 6.50 (1H, d, J=5.4
Hz), 7.36 (5H, s), 7.75 (1H, d, J=5.4 Hz), 9.88 (1H, s).
Example Bb
To an ice cooled aqueous (465 ml) solution of sodium chlorite (38.4
g, 424 mmol) and sulfamic acid (54.9 g, 566 mmol), acetone (465 ml)
solution of compound B (46.5 g, 202 mmol) was added and the mixture
was stirred for 40 minutes at room temperature. After removing
acetone in vaccuo, precipitates were collected by filtration and
washed with cold water. Compound C (42.8 g, 86%) was obtained as
colorless crystal.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 5.12 (2H, s), 6.54 (1H, d,
J=5.6 Hz), 7.33-7.46 (5H, m), 8.20 (1H, d, J=5.6 Hz).
Example Bc
An ethanol (17 ml) solution of allylamine (13.2 g 231 mmol) was
added to an ethanol (69 ml) suspension of compound C (17.2 g, 70
mmol), then the mixture was stirred for 4.5 hours at 50.degree. C.
and for 3 hours at 75.degree. C. To the cooled reaction mixture, 2N
hydrochloric acid and ice were added and precipitates were
collected by filtration. Compound D was obtained as colorless
crystal.
.sup.1H-NMR (CDCl.sub.3) .delta.: 4.37 (2H, brs), 4.95 (2H, s),
5.26-5.39 (2H, m), 5.81-5.94 (1H, m), 6.32 (1H, dd, J=0.8, 7.2 Hz),
7.29-7.37 (3H, m), 7.48-7.51 (2H, m), 7.99 (1H, dd, J=0.8, 7.6 Hz),
8.11 (1H, brs).
Example Bd
To an acetonitrile (146 ml) suspension of compound D (14.6 g, 51
mmol), 1,8-diazabicyco[5.4.0]undec-7-ene (15.5 g, 102 mmol) and
methyl iodide (18.2 g, 128 mmol) were added and the mixture was
stirred for 15 hours at room temperature. After evaporating
solvent, the residue was purified by silica gel column
chromatography (chloroform/methanol). Compound E (14.2 g, 93%) was
obtained as colorless solid.
.sup.1H-NMR (CDCl.sub.3) .delta.: 3.75 (3H, s), 4.40 (2H, d, J=5.7
Hz), 5.16-5.35 (2H, m), 5.29 (2H, s), 5.81-5.94 (1H, m), 6.62 (1H,
d, J=7.5 Hz), 7.27-7.42 (6H, m).
Example Be
To a diethyl ether (390 ml) solution of compound E (13.3 g, 44
mmol), potassium osmate (VI) dihydrate (1.62 g, 4.4 mmol) and
sodium metaperiodate (28.1 g, 132 mmol) were added. The mixture was
stirred for 2.5 hours at room temperature and precipitates were
collected by filtration. Collected solid was dissolved in
chloroform-methanol and insoluble particles were filtered off.
Concentration in vaccuo gave crude product of compound F (14.3
g).
1H NMR (DMSO-d.sub.6) .delta.: 3.23 (3H, s), 3.82 (3H, s), 3.87
(2H, t, J=4.4 Hz), 4.62 (1H, dd, J=11.7, 4.8 Hz), 5.11 (2H, s),
6.31 (1H, d, J=7.5 Hz), 6.78 (1H, d, J=6.6 Hz), 7.33-7.40 (5H, m),
7.64 (1H, d, J=7.5 Hz).
Example Bf
To chloroform (108 ml) and methanol (12 ml) solution of compound F
(11.7 g, crude product), 3-aminopropanol (2.77 g, 36.9 mmol), and
acetic acid (1.2 ml) were added and the mixture was stirred for 90
minutes at 70.degree. C. After concentrating in vaccuo, the residue
was purified by silica gel column chromatography
(chloroform/methanol). Compound G (8.48 g, 72% for 2 steps) was
obtained as colorless cryatal.
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.54-1.64 (1H, m), 1.85-2.01 (1H,
m), 3.00 (1H, dt, J=3.6, 12.9 Hz), 3.74 (1H, dt, J=2.7, 12.3 Hz),
3.93 (1H, dd, J=5.1, 13.5 Hz), 4.07-4.21 (2H, m), 4.63-4.69 (1H,
m), 4.94 (1H, t, J=4.8 Hz), 5.25 (2H, dd, J=10.2, 24.6 Hz), 6.56
(1H, d, J=7.5 Hz), 7.22-7.38 (5H, m), 7.63-7.66 (2H, m).
Example Bg
To acetic acid (93 ml) solution of compound G (6.1 g, 18.7 mmol),
acetic acid (31 ml) solution of bromine (1.44 ml, 28.0 mmol) was
added dropwisely during 15 minutes. The mixture was stirred for 3
hours at room temperature. After addition of 5% aqueous sodium
hydrogen sulfite (8 ml), 2N sodium hydroxide (500 ml) was added
dropwisely during 20 minutes. Precipitates were collected by
filtration and washed with mixture of dichloromethane and
diisopropyl ether. Compound H (6.02 g, 79%) was obtained as
colorless crystal.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.55-1.74 (2H, m), 3.12 (1H,
dt, J=3.0, 12.3 Hz), 3.84 (1H, dt, J=2.7, 11.7 Hz), 4.00-4.05 (1H,
m), 4.20-4.26 (1H, m), 4.40-4.46 (2H, m), 5.03 (2H, s), 5.15-5.17
(1H, m), 7.31-7.40 (3H, m), 7.56-7.58 (2H, m), 8.39 (1H, s).
Example Bh
To dimethyl sulfoxide (1.42 ml) solution of compound H (71 mg,
0.175 mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg,
0.035 mmol), 4-fluorobenzyl amine (0.06 ml, 0.525 mmol) and
diisopropyl amine (0.15 ml, 0.875 mmol) were added, then the
mixture was stirred under carbon monoxide atmosphere for 5 hours at
80.degree. C. After cooling, saturated aqueous ammonium chloride
was added and the mixture was extracted with ethyl acetate. The
extract was washed with water and dried with anhydrous sodium
sulfate. Solvent was removed in vaccuo and the residue was purified
with silica gel column chromatography (ethyl acetate/methanol).
Compound I (74.5 mg, 89%) was obtained as colorless crystal.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.58-1.74 (2H, m), 3.10-3.18
(1H, m), 3.80-3.88 (1H, m), 4.02-4.07 (1H, m), 4.43-4.59 (5H, m),
5.05 (2H, s), 5.20 (1H, t, J=3.9 Hz), 7.13-7.19 (2H, m), 7.32-7.40
(5H, m), 7.56-7.59 (2H, m), 8.61 (1H, s).
Example C
Synthesis of methyl
5-bromo-1-[2-hydroxy-2-(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4--
dihydro-2-pyridinecarboxylate (in equilibrium with the
corresponding aldehyde)
This Example C shows a refunctionalization of a compound 6 as shown
above in Example 1 (of formula (VI)), including a bromination at
the Fe position, to yield final products 20 and 21 (of formula
(I)). Such compounds with Br at the Fe position can be reacted as
in Examples 1 and 2 to add the R.sup.2--X--NR.sup.1--C(O)--
sidechain.
##STR00036##
Example Ca
Methyl
1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-p-
yridinecarboxylate
##STR00037##
A reactor was charged with
1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridin-
ecarboxylic acid 6 (4.302 kg, 13.47 mol) followed by charging with
NaHCO.sub.3 (1.69 kg, 20.09 mol) and 242 g of deionized water. To
this was added 21.4 kg of NMP and the mixture was stirred and
temperature brought to 28-35.degree. C. Dimethyl sulfate (2.34 kg,
18.30 mol) was added dropwise via an addition funnel to the
reaction mixture over 1-3 hours keeping the temperature at
28-33.degree. C. The slurry was agitated at this temperature for 14
h. When deemed complete, the reaction mixture was cooled to
5.degree. C. or below and the mixture was neutralized to pH 6 by
the addition of HCl (561 mL of conc HCl in 2806 g of deionized
water). The reaction vessel was slowly charged with cold 20% brine
solution composed of 8.7 kg NaCl, 20 kg of deionized water and 14.8
kg of ice at a maximum temperature of 10.degree. C. The mixture was
agitated at 0-10.degree. C. for 2.5 h. The slurry was filtered
under vacuum and the cake washed with 15 kg of deionized water two
times. The wet solid product was dried at 45-55.degree. C. under
vacuum until constant weight was obtained. The desired product
methyl
1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridin-
ecarboxylate 7 was obtained as a light yellow solid (3.77 kg,
99.42% purity by HPLC, 84%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 7.60 (d, J=7.5 Hz, 1H), 7.36 (m, 5H), 6.28 (d, J=7.5 Hz,
1H), 5.23 (d, J=5.4 Hz, 0.1H), 5.10 (Abq, J=10.8 Hz, 2H), 4.85 (m,
1H), 3.98 (dd, J=14.3, 2.4 Hz, 1H), 3.79 (s, 3H), 3.70 (dd, J=14.3,
9.0 Hz, 1H), 3.58 (m, 1H), 3.23 (m, 1H).
Example Cb
Methyl
5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dih-
ydro-2-pyridinecarboxylate
##STR00038##
A reactor was charged with (3.759 kg, 11.27 mol) of methyl
1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridin-
ecarboxylate 7 and 18.8 L of DMF. To this agitated mixture at
18-20.degree. C. was added N-bromosuccinimide (2.220 kg, 12.47 mol)
over 20 minutes via a powder funnel. The resultant mixture was
stirred at rt for 16 h. At this time less than 1% of starting
material was present by HPLC. The mixture was worked up in half
batches by cooling to 10.degree. C. and added an ice/water mixture
(12 kg ice in 35 kg deionized water) and the mixture was agitated,
then filtered. This was repeated for the second half of the batch.
The combined filter cake was washed with 14 L of water and dired in
a vacuum oven to provide 4.033 kg of methyl
5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-
-pyridinecarboxylate 19 (91.6%) as an off-white powder of 99.2%
HPLC purity. .sup.1H NMR (300 MHz, Methanol-d.sub.4) .delta. 8.21
(s, 1H), 7.41-7.33 (m, 5H), 5.16 (s, 2H), 4.17 (dd, J=14.3, 2.4 Hz,
1H), 3.90 (dd, J=14.3, 9.0 Hz, 1H), 3.81 (s, 3H), 3.78 (m, 1), 3.52
(dd, J=11.3, 4.8 Hz, 1H), 3.41 (dd, J=11.3, 6.3 Hz, 1H).
Example Cc
Methyl
5-bromo-1-[2-hydroxy-2-(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)ox-
y]-1,4-dihydro-2-pyridinecarboxylate (in equilibrium with the
corresponding aldehyde)
##STR00039##
A reactor was charged with sodium periodate (1.67 kg, 7.8 mol) and
44 L of deionized water. To the agitated mixture was added 8.5 kg
of ice. This was stirred until all the ice melted and the mixture
temperature was 1.4.degree. C. To this was added methyl
5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-
-pyridinecarboxylate 19 (2.73 kg, 6.62 mol) via a powder addition
funnel. The mixture was allowed to warm to rt and the slurry was
stirred for 16 h. A sample was monitored by .sup.1H NMR and showed
the disappearance of starting material. The mixture was filtered
and the cake washed with 20 kg of deionized water. This was
repeated until a negative starch/iodide paper result was obtained
(4.times.20 L washes). The solids were dried in a vacuum oven at
45-55.degree. C. to provide methyl
5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2--
pyridinecarboxylate 20 (2.176 kg, 88%) as a mixture with the
corresponding aldehyde form 21. Purity was determined to be 99.5%
by HPLC. .sup.1H NMR (300 MHz, acetone-d.sub.6) .delta. 8.12 (s,
1H), 7.49-7.30.degree.(m, 5H), 5.56 (dd, J=6.0, 2.4 Hz, 1H), 5.23
(m, 1H), 5.20 (s, 2H), 3.97 (d, J=5.1 Hz, 2H), 3.87 (s, 3H).
Example 2
Methyl
5-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-1-[2-hydroxy-2-(met-
hyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylat-
e (in equilibrium with the corresponding aldehyde)
This Example shows a reaction of a compound 5 of formula (II) with
one of (III) in step i) and a refunctionalization step ii) of
compounds of formula (V) (compounds 22, 23, 24 and 25) in producing
compounds of formula (I).
##STR00040##
Example 2a
1-[2,2-Bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyri-
dinecarboxylic acid
##STR00041##
To a flask (1 L) charged with 500 mL of anhydrous ethanol was added
49.2 g (0.2 mol) of
4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid 5. The
suspension was slowly heated to 55-60.degree. C. before addition of
2-amino-acetaldehyde-dimethylacetal (84.1 g, 0.8 mole). The
reaction was then brought up to 65.degree. C. and further stirred
for 18 hours. The solvent was removed under reduced pressure to
produce
1-[2,2-Bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyr-
idinecarboxylic acid 22 (crude) as brown oil, which was used for
the next step directly.
Example 2b
Methyl
1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-
-2-pyridinecarboxylate
##STR00042##
Crude
1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-
-2-pyridinecarboxylic acid 22 obtained as above was dissolved in
DMF (500 mL). To this solution was added NaHCO.sub.3 (50.5 g, 0.6
mole). The suspension was stirred vigorously with a mechanic
stirrer while CH.sub.3I in TBME (2.0 M, 300 mL) was introduced by
addition funnel over 30 minutes. After addition, the reaction was
stirred overnight at room temperature. The reaction mixture was
then diluted with EtOAc (.about.1.5 L) and washed with water and
brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4.
Evaporation of solvents gave methyl
1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyr-
idinecarboxylate 23 as brown oil, which was used directly for the
next step.
Example 2c
Methyl
1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-
-dihydro-2-pyridinecarboxylate
##STR00043##
A 2 L flask equipped with a mechanic stirrer were charged with
methyl
1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyr-
idinecarboxylate 23 as obtained above and 500 mL of
dichloromethane. To this flask was added NBS (30 g, 0.17 mole)
portion-wise. The reaction was stirred at room temperature until
its completion (monitored by TLC, .about.6 hours). The mixture was
then diluted with dichloromethane and washed with NaHCO.sub.3 (ss).
The organic phase was dried over Na.sub.2SO.sub.4 before
evaporation of the solvents. The crude product was purified by
column chromatargraphy (silcal gel, EtOH/DCM: 0-40%) to afford
methyl
1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihyd-
ro-2-pyridinecarboxylate 24 as a light brown solid (50 g, 60% over
three steps). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.7
(s, 1H), 7.4 (m, 2H), 7.3 (d, J=7.9 Hz, 3H), 5.3 (s, 2H), 4.4 (s,
1H), 3.8 (d, J=4.8 Hz, 2H), 3.8 (s, 3H), 3.4 (s, 6H). LC-MS
(M+H.sup.+): calcd 426, obsd 426.
Example 2d
Methyl
1-[2,2-bis(methyloxy)ethyl]-5-({[(2,4-difluorophenyl)methyl]amino}c-
arbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate
##STR00044##
A pressure vessel was charged with methyl
1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihyd-
ro-2-pyridinecarboxylate 24 (6.4 g, 15 mmol),
2,4-difluorobenzylamine (3.2 g, 22.5 mmol), K.sub.3PO.sub.4 (9.45
g, 45 mmol), Pd(OCOCF.sub.3).sub.2 (398 mg, 1.2 mmol), Xantophos
(694 mg, 1.2 mmol) and toluene (200 mL). The mixture was purged by
CO (4.times.) before being heated to 100.degree. C. for 22 hours
under CO atmosphere (60 psi). After cooled down to the room
temperature, the solids were filtered off through celite and washed
with EtOAc. The filtrate was concentrated and the residual was
purified by column chromatography (silical gel, EtOA/hexane 0-80%)
to afford methyl
1-[2,2-bis(methyloxy)ethyl]-5-({[(2,4-difluorophenyl)methyl]amino}carbony-
l)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 25
as a light brown oil (4.7 g, 61%).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 10.4 (m, 1H), 8.4
(s, 1H), 7.4 (m, 6H), 6.8 (d, J=9.3 Hz, 2H), 5.3 (s, 2H), 4.6 (d,
J=5.7 Hz, 2H), 4.5 (s, 1H), 4.0 (d, J=4.8 Hz, 2H), 3.8 (s, 3H), 3.4
(s, 6H). LC-MS (M+H.sup.+): calcd 517, obsd 517.
Example 2e
Methyl
5-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-1-[2-hydroxy-2-(met-
hyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylat-
e (in equilibrium with the corresponding aldehyde)
##STR00045##
Methyl
1-[2,2-bis(methyloxy)ethyl]-5-({[(2,4-difluorophenyl)methyl]amino}-
carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate
25 (11.6 g) was treated with 90% formic acid (250 mL) at 40.degree.
C. for .about.12 hours (monitored by LC-MS). After the solvents
were evaporated at <40.degree. C., the residue was re-dissolved
in EtOAc (.about.1 L) and the resulting solution was washed with
NaHCO.sub.3 and brine. The organic phase was then dried over
Na.sub.2SO.sub.4. After evaporation of solvents, the titled
compounds 26 and 27 were obtained as an approximate 80/20
equilibrium mixture (10.57 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.3 (m, 1H), 9.47 (s, aldehyde-H. .about.0.2H)), 8.4
(m, 1H), 7.3 (s, 6H), 7.2 (m, 1H), 7.0 (m, 1H), 6.3 (m, 2H), 5.1
(s, 3H), 4.9 (m, 1H), 4.5 (m, 3H), 3.9 (m, 2H), 3.8 (s, 3H). LC-MS,
for 26 (M+H.sup.+), calcd 503, obsd 503; for 27
(M+H.sub.2O+H.sup.+), cald 489, obsd 489.
Example CC
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,-
9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyra-
zine-8-carboxamide
##STR00046##
Example CCa
(4aS,13aR)-8-Bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-py-
rido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-9,11-dione
(DD). A reactor was charged with [(2R)-2-pyrrolidinylmethyl]amine
(0.75 kg) and 4.6 L of DMF was added followed by 0.45 kg of glacial
acetic acid. Acetonitrile (41.4 L) was then added and the mixture
was agitated for 15 minutes. To the reaction mixture was added
methyl
5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2--
pyridinecarboxylate (2.30 kg). After stirring for 20 minutes at
ambient temperature, the mixture was heated at 75-85.degree. C.
until the bromide starting material was consumed by HPLC analysis
(about 6 hrs). Upon completion, the mixture was cooled until the
refluz subsided and then charged with 6.9 L of methanol and the
mixture was heated at reflux for about 45 minutes then cooled to
15.degree. C. and filtered and dried to provide
(4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahyd-
ro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-9,11-dione
(1.93 kg, 78%) as a white solid.). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 8.65 (m, 1H), 7.54 (m, 2H), 7.33 (m, 3H),
5.15 (d, 1H), 4.99 (d, 1H), 4.60 (m, 1H), 4.36 (m, 1H), 4.03 (m,
1H), 3.90 (m, 1H), 3.65 (m, 1H), 3.06-2.84 (m, 3H), 1.92-1.60 (m,
4H).
Example CCb
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)o-
xy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':
3,4]imidazo[1,2-d]pyrazine-8-carboxamide. A reaction vessel was
charged with
(4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro--
1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-9,11-dione
(1.4 kg), 2,4-difluorobenzylamine (705 g), Hunigs base (1.4 L),
dppf (60 g) and DMSO (12 L). The mixture was degassed with high
purity nitrogen 4 times. To this mixture was added palladium (II)
trifluoroacetate (18 g) in DMSO (2 L). The mixture was again
degassed 3 times with high purity nitrogen and then purged with CO
3 times and left under a 45 psi atmosphere of CO. The mixture was
heated at 80.degree. C. under 45 psi CO until the reaction appeared
complete by HPLC (24 hrs). The mixture was cooled to rt and slowly
transferred to an ice slurry of ammonium chloride. The mixture was
filtered and washed with water and isopropanol. The residue was
recrystallized from isopropanol to provide
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)o-
xy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imida-
zo[1,2-d]pyrazine-8-carboxamide (952 g, 56%). Recrystallization of
the mother liquor from isopropanol produced a second crop of
crystals of the desired product in the amount of 327 g (19%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 10.44 (m, 1H), 8.55
(s, 1H), 7.56-7.07 (m, 8H), 5.18 (d, 1H), 5.03 (d, 1H), 4.62-4.54
(m, 4H), 4.06-3.60 (m, 3H), 3.20-2.80 (m, 3H), 1.93-1.60 (m,
4H).
Example CCc
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5-
,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':
3,4]imidazo[1,2-d]pyrazine-8-carboxamide. A pressure reaction
vessel was charged with
(4aS,13aR)--N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)o-
xy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imida-
zo[1,2-d]pyrazine-8-carboxamide (950 g), 192 g of palladium on
carbon (50% wet), ethanol (9.5 L) and concentrated ammonium
hydroxide (124 mL). The mixture was degassed with nitrogen 3 times
and then placed under 50 psi of hydrogen until the reaction was
complete. The mixture was degassed again with nitrogen and then
filtered through Celite. The cake was extracted with refluxing
dichloromethane and then filtered again. The combined filtrates
were concentrated to a small volume (4 L), azeotroped with ethanol
(28.5 L) to a final volume of 9 L. The slurry was filtered and
washed with ethanol and dried to produce
(4aS,13aR)--N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5-
,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyr-
azine-8-carboxamide (616 g, 78.4%) as a white solid. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 10.37 (m, 1H), 8.42 (s, 1H),
7.41-7.05 (m, 3H), 4.72-4.53 (m, 4H), 4.05 (m, 1H), 3.86 (m, 1H),
3.70 (m, 1H), 3.16 (m, 1H), 2.88 (m, 2H), 1.92-1.60 (m, 4H).
* * * * *